Abstract
DNA replication timing is tightly regulated during S-phase. S-phase length is determined by DNA synthesis rate, which depends on the number of active replication forks and their velocity. Here, we show that E2F-dependent transcription, through E2F6, determines the replication capacity of a cell, defined as the maximal amount of DNA a cell can synthesise per unit time during S-phase. Increasing or decreasing E2F-dependent transcription during S-phase increases or decreases replication capacity, and thereby replication rates, thus shortening or lengthening S-phase, respectively. The changes in replication rate occur mainly through changes in fork speed without affecting the number of active forks. An increase in fork speed does not induce replication stress directly, but increases DNA damage over time causing cell cycle arrest. Thus, E2F-dependent transcription determines the DNA replication capacity of a cell, which affects the replication rate, controlling the time it takes to duplicate the genome and complete S-phase.
Highlights
DNA replication timing is tightly regulated during S-phase
We first investigated if an overall increase in E2Fdependent transcription during S phase affects the timely duplication of the genome
We have previously established that E2F6 knockdown maintains E2F-dependent transcription at a high level during S phase in T98G cells[20]
Summary
DNA replication timing is tightly regulated during S-phase. S-phase length is determined by DNA synthesis rate, which depends on the number of active replication forks and their velocity. The presence of dormant origins allows origin usage to change according to cellular context, providing plasticity to the genome duplication process The time it takes to complete genome duplication, and S-phase length, depends on the DNA synthesis rate. We speculate that limiting the replication capacity of a cell would provide an elegant mechanism to regulate the global rate of replication during S phase, largely independent of the number of active replication forks. It would ensure timely completion of genome duplication and prevent potentially harmful alterations in fork speed[11]. This mechanism allows genes needed for replication to be sufficiently expressed during S phase
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